Li Qiuhui, Guo Guoqing, Chen Yuli, Lu Lu, Li Hanyang, Zhou Zihan, Guo Jiahao, Gan Xiongkang, Hu Yanming, Li Qiunuo, Sun Ming, Liu Xianghua
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China.
Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215001, China.
Adv Sci (Weinh). 2024 Dec;11(46):e2407012. doi: 10.1002/advs.202407012. Epub 2024 Oct 24.
The context of long noncoding RNAs (lncRNAs) contains many unannotated open reading frames (ORFs). These ORFs potentially encode novel proteins or peptides with crucial roles in various human cancers, yet the translational potential of these lncRNAs and the functions of the protein products remain largely unexplored, especially in gastric cancer (GC). In this study, a comprehensive analysis is performed and identified a GC associated lncRNA known as HCP5, which contains a non-canonical ORF. Further analysis showed that HCP5-132aa, a microprotein encoded by HCP5 harboring this ORF, is highly expressed in GC cells and tissues, and can promote the proliferation of GC cells by inhibiting ferroptosis. Mechanistically, HCP5-132aa enhances the interaction between YBX1 and ELAVL1, facilitates recognition of YBX1 at the mC site in the 3'UTR of SLC7A11 and G6PD mRNA, and preserves their stability via ELAVL1. By employing a Cas9/sgRNA delivery system with AAV in vivo, effectively knocked out the HCP5-132aa and inhibition of tumor growth in a patient-derived xenograft model are achieved. These findings demonstrate that the novel protein HCP5-132aa, derived from lncRNA HCP5, mediates the repression of ferroptosis, thereby driving the progression of GC and identifying a new potential therapeutic target for its treatment.
长链非编码RNA(lncRNAs)的背景中包含许多未注释的开放阅读框(ORFs)。这些ORFs可能编码在各种人类癌症中起关键作用的新型蛋白质或肽,但这些lncRNAs的翻译潜力以及蛋白质产物的功能在很大程度上仍未被探索,尤其是在胃癌(GC)中。在本研究中,进行了全面分析并鉴定出一种与GC相关的lncRNA,称为HCP5,它包含一个非规范的ORF。进一步分析表明,由携带该ORF的HCP5编码的微蛋白HCP5-132aa在GC细胞和组织中高表达,并可通过抑制铁死亡促进GC细胞的增殖。机制上,HCP5-132aa增强了YBX1和ELAVL1之间的相互作用,促进YBX1在SLC7A11和G6PD mRNA的3'UTR中mC位点的识别,并通过ELAVL1保持它们的稳定性。通过在体内使用带有腺相关病毒(AAV)的Cas9/sgRNA递送系统,有效敲除了HCP5-132aa,并在患者来源的异种移植模型中实现了肿瘤生长的抑制。这些发现表明,源自lncRNA HCP5的新型蛋白质HCP5-132aa介导铁死亡的抑制,从而推动GC的进展,并确定了一个新的潜在治疗靶点用于其治疗。
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